The advent of highly active antiretroviral therapy (HAART) has dramatically decreased the death rate due to HIV-1 infection in AIDS patients. However, the efficacy of HAART on HIV-1 associated complication of the central nervous system has remained at a lower level. Most notably, the incidence of white matter disease such as Progressive Multifocal Leukoencephalopathy (PML) appears to be less affected. Some studies show that only half of the PML patients benefit from HAART and show improved survival. Alarmingly, with the advent of HAART, PML remains a fast progressing disease in some patients, whereas other groups of patients show signs of PML with a slower progression. In addition, several new cases of anew leukoencephalopathy with no sign of active JCV replication, named non-determined leukoencephalopathy (NDLE), have been clinically diagnosed among AIDS patients under HAART treatment. In this R21 pilot research proposal, we will perform comprehensive longitudinal clinical, virological, and immunological studies on several AIDS patients under HAART exhibiting leukoencephalopathy to determine if a new variant of JCV is associated with slower progressing PML and if the new leukoencephalopathy is the result of imbalanced expression of cytokines and immunomodulators. The use of DNA microarray technology will provide us with compelling information on the profile of cellular gene expression in immune cells of AIDS patients with fast and slow progressing PML, as well as those exhibiting NDLE. [unreadable] [unreadable] [unreadable]